Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis.

Malmström, Vivianne; Michaëlsson, Erik; Burkhardt, Harald; Mattsson, Ragnar; Vuorio, Eero; Holmdahl, Rikard

doi:10.1073/pnas.93.9.4480

Cited by 76 publications

(104 citation statements)

References 43 publications

(37 reference statements)

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“…These humanized mice were backcrossed for 10 generations onto the C3H.Q and B10.Q backgrounds and subsequently intercrossed before being used in experiments. Before intercrossing, the HuCII transgene was also exchanged for the MMC transgene (20) by crossing with MMC.C3H.Q or MMC.B10.Q.Ncf1* / * mice (21,22) (i.e., MMC-transgenic mice that also lack a functional Ncf1 gene, therefore lacking a functional phagocytic NADPH oxidase complex 2). The MMC transgene is a mutated mouse CII gene in which the amino acid at position 266 has been changed from an aspartic acid to a glutamic acid, thereby expressing the rat/human CII [259][260][261][262][263][264][265][266][267][268][269][270][271][272][273] epitope in a CII-specific manner.…”

Section: Methodsmentioning

confidence: 99%

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Batsalova¹,

Dzhambazov²,

Mehlen³

et al. 2010

Arthritis & Rheumatism

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Section: Methodsmentioning

confidence: 99%

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Batsalova¹,

Dzhambazov²,

Mehlen³

et al. 2010

Arthritis & Rheumatism

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“…Immunization with heterologous (rat) CII leads to a predominant activation of T-cells responding to the heterologous CII 256-270 peptide and not to the corresponding mouse CII 256-270 peptide. The heterologous peptide is immunodominant as shown by the lack of immunogenicity of rat CII in transgenic mice expressing this peptide in type I collagen [12]. As expected from the high degree of sequence conservation of CII, the same peptide is predominantly recognized also after immunization with bovine [13] and human CII [14].…”

Section: Introductionmentioning

confidence: 99%

“…This minor difference has severe consequences for the susceptibility to CIA [12]. Immunization with heterologous (rat) CII leads to a predominant activation of T-cells responding to the heterologous CII 256-270 peptide and not to the corresponding mouse CII 256-270 peptide.…”

Section: Introductionmentioning

confidence: 99%

Arthritis Susceptibility in Mice Expressing Human Type II Collagen in Cartilage

Malmström

Lun

et al. 1997

Scand J Immunol

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Collagen type II (CII) induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis. Induction with non-self (e.g. human) CII induces severe arthritis whereas the mice are less susceptible to induction with self CII (i.e. mouse). To analyse whether an autoimmune response to human CII can develop and is pathogenic the authors have established transgenic mice expressing human CII in cartilage and backcrossed them into two different gene backgrounds susceptible to CIA (DBA/1 and C3H.Q). The transgenic human CII expression was restricted to cartilage and did not disturb cartilage morphology or lead to chondrodystrophy. In addition, development of stress-induced arthritis was not affected by the transgene. The cartilage specific expression of human CII reduced, but did not eliminate, the susceptibility to CIA irrespective of the species source (human, bovine, chick, rat) of CII used for immunization. A common denominator between these heterologous CII in comparison with mouse CII is the previously defined CII 256-270 epitope. An expression level dependent T-cell tolerance was seen in this epitope as well as to the entire CII. However, all human transgenic mouse lines could still mount significant autoreactive T-and B-cell responses. Approximately 10% of the transgenic mice developed arthritis after immunization with human CII. These findings show, therefore, that cartilage-located human CII induce tolerance but can nevertheless be a target for development of arthritis.

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“…Interestingly, a peptide from the same region, at positions 261-271, binds to RA-associated DR4 and DR1 molecules, and transgenic expression of these class II molecules in mice renders them susceptible to CIA (12)(13)(14)(15)(16). In addition, in both mice and men, T cells are exposed to cartilage-derived CII (17,18) and recognize the same post-translational modified O-linked carbohydrates on this peptide (19). Thus, the observations mentioned above indicate that the structural recognition patterns are shared to a large extent between mouse and man.…”

mentioning

confidence: 99%

“…This question is strongly linked to tolerance, and we addressed it by taking advantage of the observation that the amino acid sequence of mouse CII differs at position 266, i.e., within the immunodominant 260 -270 peptide, in which the mouse has an aspartic acid, whereas other species have a glutamic acid. The expression of CII with this position mutated in the mouse, the transgenic MMC mouse, induces partial tolerance with anergized T cells and reduced frequency of arthritis (17). We have now investigated the importance of the non-MHC genetic background for induction of tolerance and arthritis susceptibility.…”

mentioning

confidence: 99%

Genetic Control of Tolerance to Type II Collagen and Development of Arthritis in an Autologous Collagen-Induced Arthritis Model

Bäcklund

Nandakumar

Bockermann

et al. 2003

The Journal of Immunology

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T cell recognition of the type II collagen (CII) 260–270 peptide is a bottleneck for the development of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. We have earlier made C3H.Q mice expressing CII with glutamic acid instead of aspartic acid at position 266 (the MMC-C3H.Q mouse), similar to the rat and human CII epitope, which increases binding to MHC class II and leads to effective presentation of the peptide in vivo. These mice show T cell tolerance to CII, but also develop severe arthritis. The present investigation shows that non-MHC genes play a decisive role in determining tolerance and arthritis susceptibility. We bred MMC into B10.Q mice, which display similar susceptibility to CIA induced with rat CII as the C3H.Q mice. In contrast to MMC-C3H.Q mice, MMC-B10.Q mice were completely resistant to arthritis. Nontransgenic (B10.Q × C3H.Q)F1 mice were more susceptible to CIA than either of the parental strains, but introduction of the MMC transgene leads to CIA resistance, showing that the protection is dominantly inherited from B10.Q. In an attempt to break the B10-mediated CIA protection in MMC-transgenic mice, we introduced a transgenic, CII-specific, TCR β-chain specific for the CII260–270 glycopeptide, in the highly CIA-susceptible (B10.Q × DBA/1)F1 mice. The magnification of the autoreactive CII-specific T cell repertoire led to increased CIA susceptibility, but the disease was less severe than in mice lacking the MMC transgene. This finding is important for understanding CIA and perhaps also rheumatoid arthritis, as in both diseases MHC class II-restricted T cell recognition of the glycosylated CII peptide occurs.

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Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis.

Cited by 76 publications

References 43 publications

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

Arthritis Susceptibility in Mice Expressing Human Type II Collagen in Cartilage

Genetic Control of Tolerance to Type II Collagen and Development of Arthritis in an Autologous Collagen-Induced Arthritis Model

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